Dropwise Additive Manufacturing of Pharmaceutical Products Using Particle Suspensions.

The principal method of drug delivery is by oral solid doses, the production of which often necessitates multiple post-crystallization unit operations to ensure content uniformity or enhance bioavailability. As an alternative to conventional dose production methods, applications of additive manufacturing technologies based on solvent- or melt-based formulations have demonstrated the potential for improvements to process efficiency, flexibility, and dosing precision. Here we explore the use of particulate suspensions in a dropwise additive manufacturing process as a method for dosing active ingredients in crystalline form, which may be difficult to achieve via powder processing due to poor flow properties. By employing a fluid-based method, powder flow issues are alleviated and adaptation of the process to new particles/crystals is facilitated by dimensional analysis. In this work, a feasibility study was conducted using 4 active ingredient powders, each with non-ideal particle properties, and 2 carrier fluids, in which the active ingredient does not dissolve, to formulate suspensions for dose manufacturing; drug products were analyzed to show reproducibility of dosing and to assess preservation of particle size through the process. Performance across particle types is affected by particle size and shape, and is related through effects on the rheological properties of the formulation.

In situ monitoring of wet granulation using online X-ray powder diffraction.

PURPOSE: Polymorphic transformations during the wet granulation of a metastable polymorph of flufenamic acid were monitored in situ using online X-ray powder diffraction. The resulting data were used in testing a proposed process induced transformation rate model, which allows the extent and occurrence of polymorphic transformations during wet granulation to be controlled by adjusting the granulation time. METHODS: A small-scale, top mixing granulator was designed for compatibility with novel X-ray powder diffraction equipment (available from X-Ray Optical Systems of East Greenbush, NY). RESULTS: The unique polycapillary optic and X-ray source allowed the transformation of the metastable to the stable polymorph to be followed during the granulation. Following a diffraction peak each for the metastable and stable forms demonstrated that polymorphic transformations during the wetting phase of granulation follow the trends predicted by the model. CONCLUSIONS: The advanced online monitoring may allow real-time control of the process by the adjustment of process parameters, such as granulation time, and clearly qualifies as a PAT (process analytical technology).